Please note this Medicines Q&A was researched and written over 2 years ago. When using this document it is important to consider new information which may have been published.
A minor update of this Medicines Q&A has been performed in light of new manufacturers advice regarding the use of enoxaparin and tinzaparin in severe renal impairment.
- The ACCP and NICE suggest the use of UFH may be preferred over LMWHs for treatment indications in patients with severe RI i.e. a CrCl of <30ml/min.
- Important advantages of UFH compared to LMWHs are that its renal excretion is minimal, it has a relatively short half-life and its effects can be easily monitored by aPTT and rapidly reversed by protamine
- However, the majority of studies comparing LMWHs with UFH have failed to demonstrate statistically significant differences in the incidence of bleeding. One exception is a study in which dalteparin was associated with a statistically significantly lower risk of bleeding in patients with an eGFR 30-60ml/min. The difference in bleeding rates was not statistically significant in patients with an eGFR <30ml/min in this study.
- The use of UFH was associated with a significantly higher mortality rate and risk of fatal PE compared with LMWH in patients with a CrCl >60ml/min or <30ml/min, but not in those with CrCl between 30-60ml/min according to RIETE data.
- Treatment doses of some LMWHs have been used in patients with RI, however caution is required when using any LMWH in patients with any degree of RI, especially those with a CrCl <30ml/min.
- Precise information on dose adjustment is not available. The ACCP advise that if LMWH is used in patients with severe RI (CrCl <30mL/min) who require therapeutic anticoagulation, the dose should be reduced and/or anti-factor Xa monitoring should be considered
- The majority of the data surrounding LMWHs and RI relates to enoxaparin. This data cannot be extrapolated to all LMWHs because the individual LMWHs differ in their degree of accumulation in RI.
- It appears there is accumulation with treatment doses of enoxaparin in RI which increases the risk of bleeding. The risk of bleeding was shown to be increased with enoxaparin in patients with a CrCl<60ml/min, in a meta-analysis. The risk was still increased when enoxaparin dosage was adjusted according to the degree of RI.
- The manufacturers of enoxaparin recommend that it is avoided in patients with a CrCl<15ml/min. In patients with a CrCl 15ml/min to 30ml/min a dose of 1mg/kg every 24 hours is advised. However current trial data provide insufficient evidence for the efficacy and safety of this regimen. Empirically adjusting the dose of enoxaparin may put the patient at risk of sub-therapeutic levels (increasing the risk of clot formation) or supratherapeutic levels (increasing the risk of haemorrhage).
- The manufacturers of tinzaparin state that it is not recommended in patients with severe RI (<30ml/min), as dosage in this population has not been established. When required in patients with a CrCl >20ml/min, tinzaparin can be used cautiously with anti-Xa monitoring, since available evidence demonstrates no accumulation at CrCl >20ml/min
- The manufacturers of dalteparin advise dosage adjustment in patients with severe RI (which they define as CrCl<30ml/min), based on anti-factor Xa levels.
- There is evidence of an increased bleeding risk in patients with all degrees of RI with both enoxaparin and UFH, compared with those with normal renal function, but whether this rate is greater with enoxaparin versus UFH is unclear.
- Despite methodological limitations (refer to text), a large retrospective cohort study supports the use of dalteparin over UFH, due to a reduction in bleeding complications, particularly in patients with an eGFR 30-60ml/min.
- Limited data suggest that tinzaparin is less likely to accumulate in patients with RI, which some have attributed to its higher molecular weight. The IRIS study was stopped prematurely because of an increase in all-cause mortality with tinzaparin compared to UFH in patients >70 years old with RI. This could not be explained by a difference in bleeds or recurrent VTE and may reflect an imbalance of mortality risk factors at baseline. However, because of the early termination results are inconclusive in terms of clinical outcomes
- Anti-factor Xa levels are used to monitor LMWHs in patients with RI, but an effective therapeutic range or levels associated with an increased bleeding risk have not been clearly established. Studies are required to establish therapeutic levels for specific indications for each LMWH in RI.
- Large scale clinical outcome studies are urgently needed to compare the different LMWHs and UFH in patients with varying degrees of RI to determine the optimum anticoagulant strategy that minimizes the risk of bleeding complications while maintaining antithrombotic efficacy.